Propofol increases agonist efficacy at the GABAA receptor

O'Shea, Sean M.; Wong, Lily C.; Harrison, Neil L.

doi:10.1016/s0006-8993(99)02151-4

Cited by 46 publications

(36 citation statements)

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“…On the other hand, Harrison and colleagues used the combination of a partial agonist for the GABA A receptor, piperidine-4-sulfonic acid (P4S), and a mutant GABA A receptor with a gating defect, to demonstrate that isoflurane potentiates maximal P4S-evoked currents and thus acts, at least in part, by enhancing channel gating (Topf et al, 2003). In a separate report, the same research group also used a similar approach with wild-type GABA A receptors and P4S to show that propofol enhances channel gating of the GABA A receptor (O'Shea et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

Solt

Stevens²,

Davies³

et al. 2005

J Pharmacol Exp Ther

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5-Hydroxytryptamine (serotonin) (5-HT) type 3 (5-HT 3 ) receptors are members of an anesthetic-sensitive superfamily of Cys-loop ligand-gated ion channels that can be formed as homomeric 5-HT 3A or heteromeric 5-HT 3AB receptors. When the efficacious agonist 5-HT is used, the inhaled anesthetics halothane and chloroform (at clinically relevant concentrations) significantly reduce the agonist EC 50 for 5-HT 3A receptors but not for 5-HT 3AB receptors. In the present study, we used dopamine (DA), a highly inefficacious agonist for 5-HT 3 receptors, to determine whether the difference in sensitivity between 5-HT 3A and 5-HT 3AB receptors to the potentiating effects of halothane and chloroform is due to differential modulation of agonist affinity, channel gating, or both. Using the two-electrode voltage-clamp technique with 5-HT 3A and 5-HT 3AB receptors expressed in Xenopus oocytes, we found that chloroform and halothane enhanced currents evoked by receptorsaturating concentrations of DA for both receptor subtypes in a concentration-dependent manner but that the magnitude of enhancement was substantially greater for 5-HT 3A receptors than for 5-HT 3AB receptors. Isoflurane induced only a small enhancement of currents evoked by receptor-saturating concentrations of DA for 5-HT 3A receptors and no enhancement for 5-HT 3AB receptors. For both receptor subtypes, none of the three test anesthetics significantly altered the agonist EC 50 for DA, implying that these anesthetics do not affect agonist binding affinity. Our results show that chloroform, halothane, and (to a much lesser degree) isoflurane enhance channel gating for 5-HT 3A receptors and that the incorporation of 5-HT 3B subunits to produce heteromeric 5-HT 3AB receptors markedly attenuates the ability of these anesthetics to enhance channel gating.

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Section: Discussionmentioning

confidence: 99%

General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

Solt

Stevens²,

Davies³

et al. 2005

J Pharmacol Exp Ther

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“…We often encounter patients, who have lost the memory during operation after administration of sedative dose of these intravenous anesthetics while they preserved their consciousness during operation [22]. In the previous paper [15], we reported that subhypnotic but not hypnotic doses of propofol, one of non-benzodiazepine anesthetic agents, which has GABA-potentiating properties [12,23,25] In the present study, we examined the effect of anesthetics applied between CS and US presentations on the long-term CTAM using several dosages of benzodiazepine agent, midazolam and compared the effects of midazolam with those of non-benzodiazepine, propofol. Furthermore, noradrenergic system has been reported to play an important role in the memory retention [7,18,19].…”

Section: Introductionmentioning

confidence: 99%

“…In rodents, it has been reported that anterograde amnesia of an avoidance task was elicited by subhypnotic doses of the intravenous anesthetics, but retrograde amnesia was induced merely by hypnotic doses of these anesthetics [24,25,27].…”

mentioning

confidence: 99%

“…We often encounter patients, who have lost the memory during operation after administration of sedative dose of these intravenous anesthetics while they preserved their consciousness during operation [22]. In the previous paper [15], we reported that subhypnotic but not hypnotic doses of propofol, one of non-benzodiazepine anesthetic agents, which has GABA-potentiating properties [12,23,25] in mammalian central neurons, accelerate only the extinction of the long-term memory formed by the CTA. Recently, Yasoshima and Yamamoto (2005) has reported that conditioned animals did not rejected the CS transiently by a systemic -4 -injection of midazolam (1.5 mg/kg) before retention, although midazolam injection before CS did not affect acquisition and retention of CTA memory [34].…”

mentioning

confidence: 99%

“…In the present experiment, this effect was induced by both of non-benzodiazepine propofol and benzodiazepine midazolam. It has been reported that both of them activate GABA A receptor or enhance activation of GABA A receptor as GABA receptor agonist [2,13,14,23,24,25].…”

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confidence: 99%

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Effects of midazolam on acquisition and extinction of conditioned taste aversion memory in rats

Ayuse

Yoshida

et al. 2009

Neuroscience Letters

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Some intravenous anesthetic agents such as midazolam are known to induce anterograde and retrograde amnesia. We analysed the effect of midazolam by the conditioned taste aversion (CTA) acquisition and retention. After the rats were offered 0.1% sodium saccharin (Sac) as conditioned stimulus (CS), an intraperitoneal (i.p.) injection of several concentrations (5 ~ 30 mg/kg) of midazolam was followed by an i.p. injection of 0.15 M LiCl (2% of body weight) as unconditioned stimulus (US). The rats, which acquired CTA by every CS-US paradigm, strongly avoided Sac on the 1st test day after conditioning and maintained the avoidance for 3 days. We have already reported that Sac intake abruptly increased on the 2nd test day and the almost complete extinction occurred on the 3rd test day after conditioning by injection of subhypnotic dose of propofol before LiCl-injection. In contrast, we found that subhypnotic dose of midazolam suppressed not only CTA acquisition, but also CTA retention. On the other hand, an α2-adrenergic blocker, yohimbin (1 mg/kg) suppressed only the CTA retention. These results suggest that the subhypnotic doses of midazolam firstly affect the acquisition mechanism of the CTA memory (CTAM ), resulting the suppression of the retention of CTAM.Key words: midazolam ; CTA; memory; acquisition; extinction; amnesia, Yohimbin, noradrenergic system -3 -Intravenous anesthetics such as midazolam, one of benzodiazepine anesthetic agents, which possess both γ-aminobutylic acid (GABA)-like [13,29], are known to induce anterograde and retrograde amnesia in human [16,17] and rodents [24,26]. In rodents, it has been reported that anterograde amnesia of an avoidance task was elicited by subhypnotic doses of the intravenous anesthetics, but retrograde amnesia was induced merely by hypnotic doses of these anesthetics [24,25,27].Previous works using a CTA paradigm, where conditioned taste aversion memory (CTAM) related to malaise is formed when an animal consumes a novel taste such as saccharin (conditioned stimulus, CS) and then experiences the symptoms of poisoning such as LiCl (unconditioned stimulus, US) [9], show that the strong CTA is established rapidly by novel taste stimuli in a single learning procedure [5,32]. The association between the CS and the US can proceed under deep anesthesia induced by pentobarbital or ketamine when hypnotic doses of these anesthetics are administrated after CS-presentation, or subhypnotic doses of them, which do not impair drinking, was applied before CS-presentation [6,33].However, subhypnotic doses of the intravenous anesthetics are often used for disabled patients even in light operation such as extraction of teeth to sedate their hyperactivity [22,31]. We often encounter patients, who have lost the memory during operation after administration of sedative dose of these intravenous anesthetics while they preserved their consciousness during operation [22]. In the previous paper [15], we reported that subhypnotic but not hypnotic doses of propofol, one of non-benzodiazepine...

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Anesthetic sites and allosteric mechanisms of action on Cys-loop ligand-gated ion channels

Forman

Miller

2011

Can J Anesth/J Can Anesth

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The Cys-loop ligand-gated ion channel superfamily is a major group of neurotransmitter–activated receptors in the central and peripheral nervous system. The superfamily includes inhibitory receptors stimulated by GABA and glycine and excitatory receptors stimulated by acetylcholine and serotonin. General anesthetics at clinical concentrations inhibit the excitatory receptors and enhance the inhibitory receptors. The location of general anesthetic binding sites on these receptors is being defined by photoactivable analogs of general anesthetics. The muscle type nicotinic acetylcholine receptor (nAChR) is the most extensively studied, and progress is now being made with γ-aminobutyric acid type A receptors (GABAARs). There are three categories of sites, all in the transmembrane domain: (1) Within a single subunit's four-helix bundle (intrasubunit site; halothane and etomidate on the δ–subunit of AChRs); (2) Between five subunits in the transmembrane conduction pore (channel lumen sites; etomidate and alcohols on nAChR), and (3) between two subunits (subunit interface sites; etomidate between the β1 and β2/3 subunits of the GABAAR). These binding sites function allosterically. Certain conformations of a receptor bind the anesthetic with greater affinity than others. Time resolved photolabeling of some sites occurs within milliseconds of channel opening on the nAChR but not before. In GABAARs, electrophysiological data fits an allosteric model in which etomidate binds to and stabilizes the open state, increasing both the fraction of open channels and their lifetime. As predicted by the model, etomidate's channel–stabilizing action is so strong that at higher concentrations it opens the channel in the absence of agonist.

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Propofol increases agonist efficacy at the GABAA receptor

Cited by 46 publications

References 25 publications

General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

Effects of midazolam on acquisition and extinction of conditioned taste aversion memory in rats

Anesthetic sites and allosteric mechanisms of action on Cys-loop ligand-gated ion channels

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